Newron Pharmaceuticals S.p.a.

Euticals Prime European Therapeuticals Spa

Euticals Prime European Therapeutical Spa

Claudio Giordano

Erwin Waldvogel

Claudio Gianluca Pozzoli

Fabio Benedetti

Luca Giannini

The invention relates to a new process for the production and/or purification of the salt of the compound (S)-2-[4-(2-fluorobenzyloxy) benzylamino]propanamide, i.e. ralfinamide, or the respective R-enantiomer, with methane sulfonic acid in high yields and very high enantiomeric and chemical purity in the form of the crystalline anhydrous polymorph identified as form A, wherein said salt is substantially free from impurities having genotoxic effect, such as (C-C)alkanylmethanesulfonates, and residual solvents known as potential precursors thereof, such as (C-C)alkanols or esters thereof with lower alkanoic acids.

Process for the production of ralfinamide salts substantially free from impurities having genotoxic effects

The invention relates to a new process for the production and/or purification of the salt of the compound (S)-2-[4-(2-fluorobenzyloxy) benzylamino]propanamide, i.e. ralfinamide, or the respective R-enantiomer, with methane sulfonic acid in high yields and very high enantiomeric and chemical purity in the form of the crystalline anhydrous polymorph identified as form A, wherein said salt is substantially free from impurities having genotoxic effect, such as (C1-C5)alkanylmethanesulfonates, and residual solvents known as potential precursors thereof, such as (C1-C5)alkanols or esters thereof with lower alkanoic acids.

A method is described for the preparation of aryl-pyridine compounds of formula (I) by cross-coupling reaction, promoted by catalytic systems based on palladium or nickel between compounds of formula (II) and (III) in which: -Met represents Mg or Zn, &#x2014;Y represents Cl, Br, I or acetoxy, &#x2014;Z represents I, Br, Cl, triflate, sulphonate, phosphate, &#x2014;R, R, R, R, which are the same as one another or different, represent hydrogen, a linear and/or branched C-Calkyl, and/or an aryl, and/or a heteroaryl, or Rand Rand/or Rand R, taken together, form a C-Cring, an aryl and/or a heteroaryl, -A represents &#x2014;CORwhere Rrepresents hydrogen, a linear and/or branched C-Calkyl, and/or an aryl, and/or a heteroaryl, or -A represents &#x2014;CR(OR)(OR) where Rhas the meaning described above and Rand R, which are the same as one another or different, represent a linear and/or branched C-Calkyl, and/or an aryl, and/or a heteroaryl, or Rand R, joined together, represent a C-Calkyl or alkenyl. 

Process for the preparation of aryl-piridyl compounds

A process is described for the preparation of arylpyridine compounds by aryl-aryl cross-coupling reactions between a halopyridine and an arylmagnesium halide carried out in the presence of a catalytic amount of a zinc salt and a catalytic amount of palladium. The zinc salt is preferably selected from ZnCl , ZnBr and/or Zn(OAc) , while the palladium is preferably used in the form of Pd(PPh ) or Pd(OAc) &plus;4 PPh . The reaction can also be carried out in the presence of bidentate phosphines, such as, for example, 1,3-bis(diphenylphosphine)propane or 1,4-bis(diphenylphosphine)-butane. It is thus possible to obtain molar yields higher than 97% (calculated relative to the halopyridine) and a catalyticity of more than 2000.

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Milan, Italy

Claudio Giordano